EP0260537A1 - 13-Deoxy-23-oxo(keto)- und 23-imino-Derivate von 13-Deoxy-C-076-aglykon-Verbindungen - Google Patents

13-Deoxy-23-oxo(keto)- und 23-imino-Derivate von 13-Deoxy-C-076-aglykon-Verbindungen Download PDF

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EP0260537A1
EP0260537A1 EP87112859A EP87112859A EP0260537A1 EP 0260537 A1 EP0260537 A1 EP 0260537A1 EP 87112859 A EP87112859 A EP 87112859A EP 87112859 A EP87112859 A EP 87112859A EP 0260537 A1 EP0260537 A1 EP 0260537A1
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Prior art keywords
alkyl
groups
carbamoyl
halogens
optionally substituted
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French (fr)
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Goro Asato
Donald John France
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Wyeth Holdings LLC
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American Cyanamid Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/24—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof containing the groups, or; Thio analogues thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
    • A01N47/34—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N< containing the groups, e.g. biuret; Thio analogues thereof; Urea-aldehyde condensation products
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/195—Antibiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics

Definitions

  • the present invention relates to new 23-oxo (keto) and 23-imino derivatives of the compounds collectively defined as 13-deoxy-C-076 aglycones.
  • the C-076 antibiotics preferably are produced by the fermentation of the microorganism Streptomyces avermitilis with the 13-deoxy-C-076 aglycone compounds having been disclosed.
  • the C-076 compounds are complex macrolides which have a 23-hydroxy substituent.
  • the selective oxidation of this 23-hydroxy group to a 23-oxo group and the subsequent derivatization of the oxo group to afford 23-imino derivatives are the subject matter of the present invention.
  • These 23-oxo and 23-imino derivatives of the 13-deoxy-C-076 aglycone compounds are useful for the prevention, treatment or control of helmintic, ectoparasitic, insect, acarid and nematode infections and infestations in warm-blooded animals and agricultural crops.
  • the present invention provides novel 23-oxo (keto) and 23-imino derivatives of the compounds designated 13-deoxy-C-076 aglycones.
  • the 13-deoxy-C-076 aglycone compounds have the following structural formula: wherein the broken line indicates a single or a double bond; R is halogen or hydrogen; R 1 is hydroxy and is present only when said broken line indicates a single bond; R 2 is isopropyl or sec-butyl; and R 3 is methoxy or hydroxy.
  • the compounds of the present invention are useful anthelmintics, ectoparasiticides, insecticides, acaricides and nematicides in treating, preventing or controlling such diseases in warm-blooded animals, such-as.poultry, cattle, sheep, swine, rabbits, horses, dogs, cats and human beings.
  • U.S. Patent 3,950,360, Aoki et al, April 13, 1976 discloses certain antibiotic substances obtained by culturing a Streptomyces microorganism, said compounds being useful as insecticides and acaricides. Further, an entire series of U.S. patents relates to certain compounds produced by the fermentation of Streptomyces avermitilis (U.S. Patent 4,171,314, Chabala et al, October 16, 1979; U.S. Patent 4,199,569, Chabala et al, April 22, 1980; U.S. Patent 4,206,205, Mrozik et al, June 3, 1980; U.S. Patent 4,310,519, Albers-Schonberg, January 12, 1982; U.S.
  • U.S. Patent 4,423,209, Mrozik, December 27, 1983 relates to the process of converting some of these less desirable components to more preferred ones.
  • British Patent Application No. 2166436 A discloses antibiotics also.
  • European Patent Application Publication No. 170,006 also discloses useful such antibiotics.
  • the present compounds or the pharmaceutically and pharmacologically acceptable salts thereof exhibit excellent and effective treatment, prevention and/or control of these serious diseases of warm-blooded animals.
  • the 13-deoxy-C-076 aglycone compounds which may act as precursors of the present compounds are represented by the following structural formula, wherin the broken line indicates a single or a double bond; R is halogen or hydrogen; R 1 is hydroxy and is present only when said broken line indicates a single bond; R 2 is isopropyl or sec-butyl; and R 3 is methoxy or hydroxy.
  • R 1 is methoxy or hydroxy
  • R 2 is isopropyl or sec-butyl
  • X is oxygen, NOR 4 , or N-NHR 5
  • R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxymethyl, benzoyl, allyl, propargyl, phenyl, CH 2 COO-alkyl (C 1 -C 4 ), N-(C 1 -C 6 alkyl)carbamoyl, N-(allyl)carbamoyl, N-(propargyl)carbamoyl, N-(phenyl)carbamoyl, N-(chlorophenyl)-carbamoyl, N-(dichlorophenyl)carbamoyl, N-(benzyl)carbamoyl, C 1 -C 6 alkanoyl, chloroacetyl, methoxy
  • a preferred group of compounds of structure (I) includes R 1 as hydroxy; R 2 as isopropyl or sec-butyl; X as oxygen.
  • NOR 4 NNH- or NNHCH 3 ; and R 4 , R s , R 7 and R 8 as described hereinabove.
  • R 1 as hydroxy
  • R 2 as isopropyl or sec-butyl
  • X as oxygen, NOR 4 , NNH- , or NNHCH 3
  • R 4 as C 1 -C 3 alkyl, N-(C 1 -C 4 alkyl)carbamoyl, N-(phenyl)carbamoyl, N-(allyl)carbamoyl, N-(4-chlorophenyl)carbamoyl, N-(benzyl)carbamoyl, C 1 -C 4 alkanoyl, chloroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl and chlorobenzoyl; and R 6 and R 7 as described hereinabove.
  • the most preferred group o of compounds of structure (I) includes R 1 as hydroxy; R 2 as isopropyl or sec-butyl; X as NOR 4 , or NNHR 5 ; R 6 and R 7 as hydrogen or C 1 -C 4 alkyl; and R 5 as C 1 -C 4 alkyl or C 1 -C 4 alkanoyl.
  • Suitable protecting groups are trisubstituted silyl groups, such as t-butyidimethylsilyl and trimethylsilyl, or trisubstituted silyloxyacetyl groups, such as t -butyldimethylsilyloxy acetyl group.
  • the protecting groups are not limited to these groups since other useful protecting groups such as acyl and substituted acyl, such as acetyl, trifluoroacetyl, chloroacetyl, trichloroacetyl, phenoxyacetyl and the like, are also useful in the present process.
  • One of the preferred protecting groups is !-butyldimethylsilyl.
  • This group is attached to the 5-hydroxyl group by reacting an unprotected 5-hydroxy F-28249 compound with t -butyldimethylsilyl chloride in the presence of a base, such as imidazole, pyridine, 4-dimethylaminopyridine, triethylamine and the like, in an aprotic solvent such as methylene chloride, toluene, ethylacetate, tetrahydrofuran, ethylenedichloride and the like.
  • a base such as imidazole, pyridine, 4-dimethylaminopyridine, triethylamine and the like
  • an aprotic solvent such as methylene chloride, toluene, ethylacetate, tetrahydrofuran, ethylenedichloride and the like.
  • HPLC high performance liquid chromatography
  • Another preferred protecting group is t-butyldimethylsilyloxy acetyl group.
  • This group is attached to the 5-hydroxyl group by combining the unprotected F-28249 compound in an aprotic solvent such as methylene chloride, toluene, ethyl acetate, tetrahydrofuran, ethylenedichloride and the like, containing a tertiary amine, such as pyridine or triethylamine, and adding the protecting agent in the form of an acid halide.
  • the reaction is conducted at a temperature of about 0°C to 30°C and is monitored by HPLC for completion.
  • the 23-hydroxyl group of the protected 13-deoxy-C-076-aglycone compound then is oxidized to the 23-oxo (or keto) group by using oxidizing agents such as pyridinium dichromate, pyridinium chlorochromate, chromic acid-dimethylpyrazole, acetic anhydride/dimethylsulfoxide, trifluoroacetic anhydride/dimethylsulfoxide, N-chlorosuccinimide/dimethylsulfoxide, oxalyl chloride/dimethylsulfoxide and the like.
  • oxidizing agents such as pyridinium dichromate, pyridinium chlorochromate, chromic acid-dimethylpyrazole, acetic anhydride/dimethylsulfoxide, trifluoroacetic anhydride/dimethylsulfoxide, N-chlorosuccinimide/dimethylsulfoxide, oxalyl chloride/d
  • the reaction is carried out at dry-ice bath temperatures (about -78°C) to room temperature (about 25°C) and is complete in about 1 to 24 hours, depending on the rate of oxidation, which is monitored by HPLC.
  • the dimethylsulfoxide oxidation procedures are carried out in the presence of a tertiary amine such as triethylamine or diisopropylethylamine.
  • Solvents such as methylene chloride, ethylenedichloride, dimethylformamide, dimethylsulfoxide and the like are used.
  • oxalyl chloride/dimethylsulfoxide in the presence of triethylamine, it is advantageous to add molecular sieves to the reaction mixture to increase the yield.
  • the oxidation may also be carried out by soil microorganisms using 100 mg to 10 g of a 23-hydroxy compound per liter of unsterilized soil at 20°C to 30°C.
  • the oxidized 23-keto compound is extracted from the soil by a solvent such as acetone, methanol or ethanol. 0
  • the silyl protecting group is removed by stirring a protected 23-deoxy-C-076 compound in a lower alkanol such as methanol at 0° to room temperature for about 0.5 hour to an hour in the presence of an acid such as p-toluenesulfonic acid.
  • the protecting group is a silyloxyacetyl group
  • the silyl group is removed with acid as described above, and the hydroxyacetyl group is cleaved with an equivalent of base such as sodium methoxide in methanol at 0° to room temperature in 0.5 hour to several hours.
  • the silyloxyacetyl group may also be removed in one step by treatment with sodium methoxide at room temperature until the reaction is complete.
  • other acyl protecting groups are removed by base treatment.
  • the imino derivatives of the 23-oxo compounds are readily prepared by standard techniques such as procedures described by S. M. McElvain in The Characterization of Organic Compounds, published by MacMillan Company, New York, 1953, pages 204-205.
  • a 23-oxo compound is stirred in alcohol, such as methanol or ethanol, or dioxane in the presence of acetic acid and an excess of the amino derivatizing agent, such as hydroxylamine hydrochloride, 0-methylhydroxylamine hydrochloride, semicarbazide hydrochloride and the like along with an equivalent amount of sodium acetate, at room temperature to 50°C.
  • alcohol such as methanol or ethanol
  • dioxane in the presence of acetic acid and an excess of the amino derivatizing agent, such as hydroxylamine hydrochloride, 0-methylhydroxylamine hydrochloride, semicarbazide hydrochloride and the like along with an equivalent amount of sodium acetate, at room temperature to 50°C.
  • the reaction is usually complete in several hours to several days at room temperature but can be readily speeded by heating.
  • the O-acyloximes or carbamoylated oximes are prepared by treating the oximes of structure (I) with acid anhydrides or isocyanates to afford (I), wherein R3 is C 1 -C 6 alkanoyl, chloroacetyl, methoxyacetyl, phenylacetyl, benzoyl, chlorobenzoyl, N-(C 1 -C 4 alkyl)carbamoyl, N-(allyl)carbamoyl, N-(propargyl)-carbamoyl, N-(phenyl)carbamoyl, N-(chlorophenyl)carbamoyl, N-dichlorophenyl)carbamoyl or N-benzyl)-carbamoyl.
  • R3 is C 1 -C 6 alkanoyl, chloroacetyl, methoxyacetyl, phenylacetyl, benzoyl, chlor
  • the reactions are conducted in inert solvents, such as methylene chloride, ethylenedichloride or dioxane, in the presence of a tertiary amine, such as triethylamine or diisopropylethylamine.
  • inert solvents such as methylene chloride, ethylenedichloride or dioxane
  • a tertiary amine such as triethylamine or diisopropylethylamine.
  • the reactions are conducted from 0°C to room temperature, but if the reactions are sluggish, heat is applied.
  • An equivalent to a slight excess of the acid anhydride is used to avoid reaction at the 5-hydroxy group.
  • novel compounds of the present invention have significant activity as anthelmintics, ectoparasiticides, insecticides, nematicides and acaricides in human and animal health areas and in agriculture.
  • helminthiasis The disease or group of diseases described generally as helminthiasis is due to infection of an animal host with parasitic worms known as helminths. Helminthiasis is a prevalent and serious economic problem in domesticated animals such as swine, sheep, horses, cattle, goats, dogs, cats and poultry. Among the helminths, the group of worms described as nematodes causes widespread and often times serious infection in various species of animals.
  • the most common genera of nematodes infecting the animals referred to above are Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostomum, Oestophagostomum, Chabertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Paracaris.
  • Certian of these such as Nematodirus, Cooperia, and Oesphagostomum primarily attack the intestinal tract while others, such as Haemonchus and Ostertagia, are most prevalent in the stomach. Still others such as Dictyocaulus are found in the lungs.
  • other parasites may be located in other tissues and organs of the body such as the heart and blood vessels, subcutaneous and lymphatic tissue and the like.
  • the parasitic infections known as helminthiases lead to anemia, malnutrition, weakness, weight loss, severe damage to the walls of the intestinal tract and other tissues and organs, and if left untreated, may result in death of the infected host.
  • the 23-oxo or -imino derivatives of 13-deoxy-C-076 aglycone compounds of this invention unexpectedly have high activity against these parasites. Additionally, they also are active against Dirofilaria in dogs, Nematospiroides, Syphacia, Aspiculuris in rodents, arthropod ectoparasites such as ticks, mites, lice, fleas, blowfly of animals and birds, the ectoparasite Lucilia sp. of sheep, biting insects and migrating dipterous larvae such as Hypoderma sp. in cattle, Gastrophilus in horses and Cuterebra sp. in rodents.
  • the compounds of the present invention also are useful in treating, preventing or controlling parasites which infect human beings as well.
  • the most common genera of parasites of the gastrointestinal tract of man are Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Trichuris, and Enterobius.
  • Other medically important genera of parasites which are found in the blood or other tissues and organs outside the gastrointestinal tract are the filiarial worms such as Wuchereria, Brugia, Onchocerca and Loa, Dracunculus and extra-intestinal stages of the intestinal worms Strongyloides and Trichinella.
  • the present compounds also are of value against arthropods parasitizing man, biting insects and other dipterous pests causing annoyance to man.
  • These compounds further are active against household pests such as the cockroach, Blattella sp., clothes moth, Tineola sp., carpet beetle, Attagenus sp., and the housefly Musca domestica.
  • Insect pests of stored grains such as Tribolium sp., Tenebrio sp., and of agricultural plants such as spider mites (Tetranycus sp.), southern army worms, tobacco budworms, boll weevils, aphids (Acyrthiosiphon sp.), migratory orthopterans such as locusts and immature stages of insects living on plant tissue are controlled by the present compounds as well as the control of soil nematodes and plant parasites such as Meloidogyne sp., which may be of importance in agriculture.
  • the compounds of the present invention may be administered orally or parenterally for animal and human usage, while they may be formulated in liquid or solid form for agricultural use.
  • Oral administration may take the form of a unit dosage form such as a capsule, bolus or tablet, or as a liquid drench where used as an anthelmintic for animals.
  • the animal drench is normally a solution, suspension or dispersion of the active compound, usually in water, together with a suspending agent such as bentonite and a wetting agent or like excipient. Generally, the drenches also contain an antifoaming agent. Drench formulations generally contain about 0.001% to 0.5%, by weight, of the active compound. Preferred drench formulations contain about 0.01% to 0.1% by weight.
  • Capsules and boluses comprise the active ingredient admixed with a carrier vehicle such as starch, talc, magnesium stearate or di-calcium phosphate.
  • capsules, boluses or tablets containing the desired amount of active compound usually are employed.
  • These dosage forms are prepared by intimately and uniformly mixing the active ingredient with suitable finely divided diluents, fillers, disintegrating agents and/or binders such as starch, lactose, talc, magnesium stearate, vegetable gums and the like.
  • suitable finely divided diluents, fillers, disintegrating agents and/or binders such as starch, lactose, talc, magnesium stearate, vegetable gums and the like.
  • Such unit dosage formulations may be varied widely with respect to their total weight and content of the active compound depending upon factors such as the type of host animal to be treated, the severity and type of infection and the weight of the host.
  • the active compound When the active compound is to be administered via an animal feedstuff, it is intimately dispersed in the feed or used as a top dressing or in the form of pellets which may then be added to the finished feed or optionally fed separately.
  • the active compounds of the present invention may be administered to animals parenterally, such as by intraruminal, intramuscular, intratracheal, or subcutaneous injection. In such an event, the active compound is dissolved or dispersed in a liquid carrier vehicle.
  • the active compound is suitable admixed with an acceptable vehicle, preferably of the vegetable oil variety such as peanut oil, cotton seed oil and the like.
  • an acceptable vehicle preferably of the vegetable oil variety such as peanut oil, cotton seed oil and the like.
  • Other parenteral vehicles such as organic preparations using solketal, propylene glycol, glycerol formal, and aqueous parenteral formulation also are used.
  • the active 23-oxo or -imino compound or compounds of the present invention are dissolved or suspended in the parenteral formulation for administration.
  • Such formulations generally contain about 0.005% to 5%, by weight, of the active compound.
  • the compounds of the present invention are primarily uses in the treatment, prevention or control of helminthiasis, they also are useful in the prevention and treatment of diseases caused by other parasites.
  • arthropod parasites such as ticks, lice, fleas, mites and other biting insects in domesticated animals and poultry are controlled by the present compounds.
  • arthropod parasites such as ticks, lice, fleas, mites and other biting insects in domesticated animals and poultry are controlled by the present compounds.
  • These compounds also are effective in treatment of parasitic diseases that occur in other animals including human beings.
  • the optimum amount to be employed will, of course, depend upon the particular compound mployed, the species ofanimal to be treated and the type and severity of parasitic infection or infestation.
  • the amount useful in oral administration of these novel compounds is about 0.001 mg to 10 mg per kg of animal body weight, such total dose being given at one time or in divided doses over a relativelyshort period of time (1-5 days).
  • the preferred compounds of the invention give excellent control of such parasites in animals by administering about 0.025 mg to 3 mg per kg of animal body weight in a single dose. Repeat treatments are given as required to combat re-infections and are dependent upon the species of parasite and the husbandry techniques being employed. The techniques for administering these materials to animals are known to those skilled in the veterinary field.
  • compositions are provided in which the active compound or compounds are intimately dispersed in an inert carrier or diluent.
  • An-inert carrier is one that will not react with the active component and that will be administered safely to animals.
  • a carrier for feed administration is one that is, or may be, an ingredient of the animal ration.
  • Suitable compositions include feed premixes or supplements in which the active compound is present in relatively large amounts, wherein said feed premixes or supplements are suitable for direct feeding to the animal or for addition to the feed either directly or after an intermediate dilution or blending step.
  • Typical carriers or diluents suitable for such compositions include distillers' dried grains, corn meal, citrus meal, fermentation residues, ground oyster shells, wheat shorts, molasses solubles, corn cob meal, edible bean mill feed, soya grints, crushed limestone and the like.
  • the active compounds are intimately dispersed throughout the carrier by methods such as grinding, stirring, milling or tumbling.
  • Compositions containing about 0.005% to 2.0%, by weight, of the active compound are particularly suitable as feed premixes.
  • Feed supplements which are fed directly to the animal, contain about 0.0002% to 0.3%, by weight, of the active compounds. Such supplements are added to the animal feed in an amount to give the finished feed the concentration of active compound desired for the treatment, prevention and/or control of parasitic diseases.
  • the desired concentration of active compound will vary depending upon the factors previously mentioned as well as upon the particular derivative employed, the compounds of this invention are usually fed at concentrations of about 0.00001 % to 0.02% in the feed in order to achieve the desired antiparasitic result.
  • the compounds also may be administered by pouring on the skin of animals via a solution.
  • the active compounds are dissolved in a suitable inert solvent, such as dimethylsulfoxide, propylene glycol of the like, alternatively in combination of solvents, for the pour-on administration.
  • the compounds of this invention also are useful in combating agricultural pests that inflict damage upon growing or stored crops.
  • the present compounds are applied, using known techniques such as sprays, dusts, emulsions and the like, to the growing or stored crops to effect protection from such agricultural pests.
  • a solution containing 0.32 g of oxalyl chloride in 5 mL of CH 2 CI 2 is cooled and stirred with 0.71 g of Type 4A molecular sieves in a dry-ice/acetone bath.
  • a mixture of 0.4 g of dimethylsulfoxide (DMSO) in 2 mL of CH 2 Cl 2 is added slowly with stirring under N 2 atmosphere.
  • 0.83 g of 5-0-t -butyldimethylsilyl-13-deoxy-C-076-B2a-aglycone in 8 mL of CH 2 CI 2 is added dropwise over 10 minutes.
  • DMSO dimethylsulfoxide
  • 5-O-t-butyldimethylsilyl-13-deoxy-23-oxo-C-076-B2b-aglycone is obtained from its corresponding alcohol. It is desilylated. Also, the oxidation of 5-0-t -butyldimethylsilyl-13-chloro-13-deoxy-C-076-B2a-aglycone affords 13-chloro-13-deoxy-23-oxo-C-076-B2a-aglycone.
  • 2-carbethoxyhydrazone, 2-carbopropoxy and 2-carbobutoxy hydrazones are prepared using the corresponding carbazates.

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EP87112859A 1986-09-12 1987-09-03 13-Deoxy-23-oxo(keto)- und 23-imino-Derivate von 13-Deoxy-C-076-aglykon-Verbindungen Ceased EP0260537A1 (de)

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US90725986A 1986-09-12 1986-09-12
US907259 1992-07-01

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EP (1) EP0260537A1 (de)
JP (1) JPS63115883A (de)
KR (1) KR880003952A (de)
AU (1) AU593383B2 (de)
CA (1) CA1301750C (de)
IE (1) IE872440L (de)
IL (1) IL83798A (de)
NZ (1) NZ221715A (de)
ZA (1) ZA876835B (de)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0307225A3 (en) * 1987-09-11 1989-10-25 American Cyanamid Company Macrolide compounds
EP0421568A1 (de) * 1989-05-17 1991-04-10 Beecham Group p.l.c. Macrolidverbindungen
WO1992008454A1 (en) * 1990-11-16 1992-05-29 Beecham Group Plc Use of avermectins and milbemycins for treating parasitic infestations in ruminants
WO1992008455A1 (en) * 1990-11-16 1992-05-29 Beecham Group Plc Avermectins and milbemycins to treat parasitic in dogs
WO2012028556A1 (en) 2010-08-31 2012-03-08 Bayer Animal Health Gmbh Macrocyclic lactones and their use and their combinations with other active substances
DE102010064245A1 (de) 2010-12-28 2012-06-28 Bayer Animal Health Gmbh Makrocylischen Lactone und deren Verwendung und deren Kombinationen mit anderen Wirkstoffen
CN103396464A (zh) * 2013-07-16 2013-11-20 河北威远动物药业有限公司 一种伊维菌素的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0002615A2 (de) * 1977-12-19 1979-06-27 Merck & Co. Inc. 13-Halo und 13-Deoxy Derivative von modifizierten Milbemycin-Verbindungen und ihre Herstellung
EP0040913A1 (de) * 1980-05-02 1981-12-02 Merck & Co. Inc. 23-Keto-substituierte Derivate von C-076-Verbindungen, ihre Herstellung und Verwendung gegen Parasite
GB2176182A (en) * 1985-04-30 1986-12-17 Glaxo Group Ltd Macrolide antibiotics

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4469682A (en) * 1983-01-28 1984-09-04 Merck & Co., Inc. Avermectin and milbemycin phosphate esters, pharmaceutical compositions, and method of use
ES8800986A1 (es) * 1985-07-27 1987-12-01 Pfizer Un procedimiento para la produccion de un nuevo derivado de avermectina
ES2054664T3 (es) * 1986-03-12 1994-08-16 American Cyanamid Co Compuestos macrolidos.
CA1296329C (en) * 1986-06-06 1992-02-25 Derek R. Sutherland Macrolide compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0002615A2 (de) * 1977-12-19 1979-06-27 Merck & Co. Inc. 13-Halo und 13-Deoxy Derivative von modifizierten Milbemycin-Verbindungen und ihre Herstellung
EP0040913A1 (de) * 1980-05-02 1981-12-02 Merck & Co. Inc. 23-Keto-substituierte Derivate von C-076-Verbindungen, ihre Herstellung und Verwendung gegen Parasite
GB2176182A (en) * 1985-04-30 1986-12-17 Glaxo Group Ltd Macrolide antibiotics

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0307225A3 (en) * 1987-09-11 1989-10-25 American Cyanamid Company Macrolide compounds
EP0421568A1 (de) * 1989-05-17 1991-04-10 Beecham Group p.l.c. Macrolidverbindungen
WO1992008454A1 (en) * 1990-11-16 1992-05-29 Beecham Group Plc Use of avermectins and milbemycins for treating parasitic infestations in ruminants
WO1992008455A1 (en) * 1990-11-16 1992-05-29 Beecham Group Plc Avermectins and milbemycins to treat parasitic in dogs
US5643886A (en) * 1990-11-16 1997-07-01 Pfizer Inc. Avermectins and milbemycins to treat parasitic infestations in dogs
AU688105B2 (en) * 1990-11-16 1998-03-05 Pfizer Inc. Method for the treatment or prophylaxis of endo- and ectoparasitic infestations in dogs
WO2012028556A1 (en) 2010-08-31 2012-03-08 Bayer Animal Health Gmbh Macrocyclic lactones and their use and their combinations with other active substances
DE102010064245A1 (de) 2010-12-28 2012-06-28 Bayer Animal Health Gmbh Makrocylischen Lactone und deren Verwendung und deren Kombinationen mit anderen Wirkstoffen
CN103396464A (zh) * 2013-07-16 2013-11-20 河北威远动物药业有限公司 一种伊维菌素的制备方法
CN103396464B (zh) * 2013-07-16 2017-04-05 河北威远动物药业有限公司 一种伊维菌素的制备方法

Also Published As

Publication number Publication date
AU7827887A (en) 1988-03-17
NZ221715A (en) 1990-10-26
IL83798A (en) 1991-08-16
CA1301750C (en) 1992-05-26
KR880003952A (ko) 1988-05-31
IE872440L (en) 1988-03-12
JPS63115883A (ja) 1988-05-20
AU593383B2 (en) 1990-02-08
ZA876835B (en) 1988-03-15

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